STRUCTURAL ORIGINS OF L(-TARTRATE INHIBITION OF HUMAN PROSTATIC ACID-PHOSPHATASE())

Acid phosphatase activity in the blood serum is usually separated into tartrate-resistant and tartrate-refractory, which is reported as the prostatic acid phosphatase level, Human prostatic acid phosphatase cry stals soaked in N-propyl-L-tartramate were used to collect x-ray diffr action data to 2.9 Angstrom resolution under cryogenic conditions. Pos itive difference electron density, corresponding to the inhibitor, was found. The quality of the electron density maps clearly shows the ori entation of the carboxylate and N-propyl-substituted amide groups. The hydroxyl group attached to C3 forms two crucial hydrogen bonds with A rg-79 and His-257, Previous crystallographic studies compiled on the t artrate-rat prostatic acid phosphatase binary complex (Lindqvist, Y., Schneider, G., and Vihko, P. (1993) J. Biol. Chem, 268, 20744-20746) e rroneously positioned D-tartrate into the active site. Modeling studie s have shown that the C3 hydroxyl group on the D(-)-stereoisomer of ta rtrate, which does not significantly inhibit prostatic acid phosphatas e, does not form strong hydrogen bonds with Arg-79 or His-257. The str ucture of human prostatic acid phosphatase, noncovalently bound in N-p ropyl-L-tartramate, is used to develop inhibitors with higher specific ity and potency than L(+)-tartrate.